The major objective of the proposed research is to assess the dose-dependent pharmacologic effects of long-term, daily cocaine administration on cardiac function in response to increased sympatho-adrenal medullary activity. Specifically, the experiments will focus on answering the following questions: 1) How do low, (5 mg/kg), medium (10 mg/kg) and high (20 mg/kg) daily doses of cocaine for 6 weeks affect exercise capacity and cardiac responsivity to the stress of endurance exercise? 2) To what extent does chronic cocaine use and abrupt withdrawal from chronic cocaine use (36 hr following cocaine) increase the vulnerability of the heart to catecholamine-induced ventricular tachyarrythmias and fibrillation? 3) How does chronic cocaine and withdrawal from cocaine affect atrial and ventricular beta- adrenergic receptor density and affinity and thus the myocardial sensitivity to stress-induced high catecholamine levels? Three experimental approaches will be utilized on different dose and treatment groups of rats: (i) intact, instrumented animals will be given a acute running bout to exhaustion- heart rate and body temperature will be monitored and time to exhaustion measured; (ii) isolated heart (Langendorff) coronary perfusion preparations will be performed to determine the myocardial response to graded doses of NE and E at 37 degrees C and 39 degrees C; (iii) radioligand binding assays and catecholamine assays will be performed on atria and ventricles of cocaine and vehicle (control) rats to determine myocardial beta-receptor density/affinity and catecholamine concentrations. Data produced by these experiments will increase basic knowledge regarding the dose- dependent pharmacological and toxicological effects of chronic cocaine use on cardiac function and the physiological capacity to perform exhaustive exercise. These data are also anticipated to provide urgently needed information on the potential risks for cardiovascular failure associated with chronic cocaine use, particularly during commonly-encountered stress conditions such as exercise, which increase adrenergic activity.